Overview:

Before a patient is identified with ovarian cancer, the disease has generally progressed dramatically. Only about a quarter of ovarian tumours are discovered before they spread beyond the ovaries. No screening tests are evident to improve the early detection and outcomes of ovarian cancer in women. It should check symptoms such as bloating, constipation, and gas in women.

Women having a family history of breast or ovarian cancer are more likely to acquire ovarian cancer than those who do not. Ovarian cancer was diagnosed in roughly 21,750 women in the United States in 2020, resulting in 13,940 fatalities.

Immunotherapy:

There have been significant advancements in utilizing various novel immunotherapeutic strategies in the therapy of multiple cancers during the last decade. Unfortunately, despite substantial efforts in this therapeutic domain, there has been no evidence of clinical value in ovarian cancer too far. Provocative research in vaccine-based therapeutics and early efficacy signals for checkpoint inhibitors hold the promise of a change in the not-too-distant future. (Tran et al., 2015)

The multi-decade quest to influence an individual cancer patient's immune system is finally going from theory to fact. Only a tiny percentage of patients saw the significant long-term therapeutic benefit. On the other hand, many reactions have been documented to last up to 30 years.

Also Read: Coping with treatment - Ovarian Cancer

Recently, a renewed focus on immune checkpoint inhibition has reignited substantial interest in a range of ways to manage the patient's immune system to eradicate cancer, or at the very least, limit its clinical manifestations for more extended periods. These clinical initiatives are making remarkable headway in various regions, including malignancies of the colon and lung, which were not previously thought to be immune-modulation targets.(Schadendorf et al., 2015) (Brahmer et al., 2012) (Oh et al., 2015)

Finally, it is becoming evident that our understanding of the best ways to manipulate the immune system, whether through immuno-reactive T-cell infusions, vaccination techniques, or immune-blocking medicines, is still in its infancy. Consider recent data revealing that the most significant benefit from immune-blocking treatments tends to occur in malignancies with the highest number of discrete mutations within the tumour., (Ansell et al., 2015)

Ovarian cancer is a good candidate for immune-modulatory treatment for a variety of reasons. To begin with, malignancy has little effect on immune-regulatory cells in the bone marrow or other parts of the body. Second, while typical ovarian cancer cytotoxic therapy can reduce the number of immune-regulatory cells, the effects are usually minor and short-lived. Furthermore, until late in the illness's natural history, it is normal for ovarian cancer patients to have a good performance status and eat well.

Furthermore, the majority of patients with ovarian cancer (even those with stage 4 illness) respond to cytotoxic treatments at first and can be expected to go for "several months" to "many years" without active treatment. This period would probably be sufficient for the requisite "activation" of immune defence systems, whether from a successful vaccination method or another type of immunological modulation.

Preclinical evidence:

The theoretical possibility for several immunotherapeutic approaches in the management of ovarian cancer, including vaccination and immune cell-based infusions, has been backed by a considerable amount of preclinical evidence.(Tse et al., 2014)(Chester et al., 2015)

The most intriguing preclinical data in this area was published more than a decade ago by a group of researchers who found that ovarian cancer patients with CD3+ T cells in their tumours (54 per cent of samples) had a 5-year overall survival (OS) of 38 per cent, compared to only 4.5 per cent in the population without evidence of t cells. 13 The absence of intratumoral T cells was also linked to a higher level of VEGF, a well-known growth stimulatory factor for ovarian cancer, according to the researchers(De Felice et al., 2015).

Immunotherapy is a treatment that boosts a person's immune system to get rid of cancerous cells. Immune checkpoint inhibitors have created a paradigm change in cancer treatment, which has included everything from cancer vaccinations to adoptive immune cell therapies. Melanoma, non-small cell lung cancer (NSCLC), renal cell carcinomas (RCC), bladder cancer, and classical Hodgkin lymphoma are among the tumours for which the FDA has approved these treatments. Evidence of complete and long-lasting tumour remission in cancers that are frequently recalcitrant to chemotherapy has fueled interest in this method.

T-cell-mediated cancer cell death necessitates the production of effector T-cells (Teff) via a multi-step process involving antigen presentation, priming, and activation, T-cell trafficking and infiltration into the tumour, cancer cell detection, and cancer cell eradication. This T-cell response is mediated by various receptors that result in inflammation or autoimmune disorders. Bothe T effector cells and T suppressor cells play a significant role in cancer cell proliferation.(Chen & Mellman, 2013)

Immune checkpoints like cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) play a critical role that results in anti-neoplastic immunity. Negative regulators, such as these receptors, dampen normal T-cell activation to prevent pathogenic overactivation. Hence increase in anti-tumour response and growth in the activity of T-cell. The CTLA-4 and PD-1 function at different points at different locations.

Also Read: Is Ovarian Cancer Curable?

The CTLA-4 immune checkpoint controls t-cell priming and activation. When the checkpoint is inhibited, auto-reactive T cells, including tumour-specific T cells, expand abnormally. Anti-CTLA inhibitors have been linked to severe immune-related side effects.

PD-1 is a cell surface receptor that regulates antigen-experienced effector T-cells and is increased during normal T-cell activation. When PD-1 interacts with one of its two known ligands, PD-L1 or PD-L2, T-cell signalling and cytokine production are inhibited, and effector T-cell numbers are reduced due to limited T-cell proliferation and increased apoptosis susceptibility. (Taube et al., 2012)(Green et al., 2010) (Atefi et al., 2014)

Trials of immune checkpoint inhibitors in ovarian cancer:

Several anti-PD-1, PD-L1, and CTLA-4 antibodies have been created and investigated in ovarian cancer patients.

Nivolumab:

Nivolumab is an FDA-approved completely humanized IgG4 monoclonal antibody that targets the PD-1 receptor in the treatment of melanoma, NSCLC, renal cell carcinoma, and Hodgkin's lymphoma. In this trial, 20 patients with platinum-resistant ovarian cancer were divided into two groups and given nivolumab with a dose of 1 or 3 mg/kg every two weeks until progression or up to 48 weeks. The primary goal was to get the best overall reaction. Eight patients (20%) had grade 3 or 4 adverse events, and two had severe adverse events. The highest overall response rate was 15%.

Two patients in each dose group experienced prolonged disease control, with two patients in the 3 mg/kg cohort obtaining a complete permanent response (CR). While the response rate matched, reported with chemotherapy in platinum-resistant cancer, the long-lasting responses were unusual in this disease and a cause for celebration, especially in a substantially pre-treated population. The expression of PD-L1 did not have a significant relationship with an objective response. Fourteen of sixteen patients with high PD-L1 expression did not respond, while one of four patients with low expression responded(Hamanishi et al., 2015).

Pembrolizumab:

Pembrolizumab is an anti-PD-1 humanized IgG4 monoclonal antibody that the FDA has approved to treat melanoma and non-small cell lung cancer. A non-randomized, multicohort phase Ib study of single-agent pembrolizumab in ovarian cancer patients (KEYNOTE-028, NCT02054806) was done [26]. PD-L1 expression in 1% of tumour nests or PD-L1 expression in the stroma were both required for eligibility. Pembrolizumab 10 mg/kg was administered every two weeks for up to 2 years, or until progression or severe side effects were seen. There were a total of twenty-six patients that received treatment. The overall response rate was 11.5 per cent, including one complete response (CR), two partial responses (PR), and 23 per cent stable illness (SD). There were some long-lasting reactions, with an average response period of 8 weeks. According to RECIST standards, the objective response rate (ORR) was 10.3 per cent [95 per cent confidence interval (CI) 2.9 to 34.2 per cent]. The 10 mg/kg dose is larger than the FDA-approved dose for unresectable or metastatic melanoma (3 mg/kg), but it is comparable to the level used for melanoma adjuvant treatment.(Bellone et al., 2018)

Durvalumab:

Durvalumab is an Fc-optimized IgG1 monoclonal anti-PD-L1 monoclonal antibody that the FDA recently designated as a breakthrough therapy for PD-L1-positive urothelial bladder cancer. In an ongoing phase I/II study of durvalumab (NCT02484404) in combination with either the PARP inhibitor, olaparib, or the VEGFR inhibitor, cediranib, there was one PR lasting >6 months in 9 evaluable ovarian cancer patients treated with durvalumab and olaparib, and one PR lasting >6 months in 5 evaluable ovarian cancer patients treated with durvalumab and cediranib. (Lee et al., 2016)

Avelumab:

Avelumab is a wholly humanized anti-PD-L1IgG1 antibody that does not disrupt the interaction between PD-1 and PD-L2. One hundred twenty-four patients with refractory or recurrent ovarian cancer (progression within six months, or after 2nd/3rdline treatment) were treated with 10 mg/kg every two weeks until progression or unacceptable toxicity in a Phase Ib. The average treatment time was 12 weeks. 6.4 per cent of patients experienced grade 3/4 adverse events, while 8.1 per cent of patients stopped taking their medication due to an adverse event.(Phase II Study of Ipilimumab Monotherapy in Recurrent Platinum-Sensitive Ovarian Cancer - Full Text View - ClinicalTrials.Gov, n.d.)

Other-checkpoints:

Atezolizumab is an FDA-approved Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that targets PD-L1. Tremelimumab is a CTLA-4 antibody that has been fully humanized. To present, no studies have reported results for ovarian cancer patients who were given atezolizumab or tremelimumab. (Ansell et al., 2015)

Future opportunities;

Predictive biomarkers have been identified. Biomarkers that can predict response to therapy, provide an early signal of efficacy, and warn of the onset of side effects are all critical needs in this sector. The most promising studies have concentrated on predicting PD-1/L1 treatment response. The categorization scheme outlined above was developed in an attempt to identify subsets of melanoma patients who would be most likely to respond to treatment (Table 1) based on indications in melanoma trials that tumour PD-L1 expression, the density of TILs, and proportion of T cells expressing PD-1 or PD-L1 was associated with response. (Taube et al., 2012)(Teng et al., 2015)

PD-L1 expression has been linked to a higher chance of benefit in several studies using anti-PD-1/L1 therapeutic antibodies in multiple tumour types, including melanoma and NSCLC [8, 32, 3840]. If at least 5% of tumour cells showed cell-surface PD-L1 staining, the tumour was classified as PD-L1 positive in these studies. Initially, scientists thought that PD-L1 negative cancers did not respond [32, 38], but subsequent studies in various tumour types have revealed objective responses in up to 20% of PD-L1 negative tumours [39, 41, 42]. Only two of 16 patients with PD-L1 tangible expression demonstrated an answer in the phase 2 nivolumab study in ovarian cancer patients, in comparison.(Taube et al., 2014)

Similarly, the avelumab trial found that 1 of 17 patients with a PD-L1 negative tumour had an objective response despite a staining cut-off level of 1% of tumour cells in ovarian cancer [28]. As a result, it's unclear if PD-L1 can be employed as a reliable biomarker for anti-PD-1/L1 therapy. PD-L1 expression, on the other hand, does not appear to affect the anti-CTLA-4 therapeutic response. In a study of previously untreated melanoma patients, PD-L1 status did not affect median PFS (mPFS) in response to ipilimumab (PD-L1 positive 3.9 months, 95 per cent CI 2.8 to 4.2 months versus PD-L1 negative 2.8 months, 95 per cent CI 2.8 to 3.1 months), but PD-L1 status did influence response to nivolumab. (Hamanishi et al., 2015), (Disis et al., 2015)

Side-effects:

Fatigue, cough, nausea, itching, skin rash, loss of appetite, constipation, joint pain, and diarrhoea are some side effects of medications:

Other, more significant side effects occur in a much smaller percentage of cases.

Infusion reactions: While receiving these medications, some persons may experience an infusion reaction. Fever, chills, flushing of the cheeks, rash, itchy skin, dizziness, wheezing, and difficulty breathing are symptoms of this condition, which is similar to an allergic reaction. If you experience any of these symptoms while taking these medications, contact your doctor or nurse immediately.

Autoimmune reactions: These medications function by eliminating one of the body's immune system's defence mechanisms. When the immune system attacks other parts of the body, severe or even life-threatening issues might occur in the lungs, intestines, liver, hormone-producing glands, kidneys, or other organs.

It's critical to notify your healthcare provider as soon as you notice any new adverse effects. If significant adverse effects occur, your therapy may be halted, and you may be given high doses of corticosteroids that help to suppress your immune system. (De Felice et al., 2015)

Conclusion:

Immune checkpoint inhibitors have sparked a surge in interest in immuno-oncology. While there is substantial evidence that the immune milieu influences outcomes in ovarian cancer, early results from clinical studies using immune checkpoint inhibitors suggest that tumour response is limited. Strategies to improve treatment results and reduce immune-related toxicity are required, and they will almost certainly necessitate tailored methods. The cancer-immune system connection can fail in several ways, resulting in insufficient anti-tumour activity.

The creation of biomarkers to detect which medicines are active in specific tumours, referred to as "personalized immunotherapy," is crucial to better understanding these areas. Some have proposed using the term "cancer immunogram" to characterize the interactions between the tumour and the immune system in individuals [91]. Clinical trials guided by biomarkers will be required to customize these methods for patients with ovarian cancer. We believe that tumour genomic profiling will need to be combined with immune profiling to provide a complete picture of a patient's tumour, allowing for better treatment selection and sequencing. ((PDF) The Role of Immune Checkpoint Inhibition in the Treatment of Ovarian Cancer, n.d.)

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Reference:

1. De Felice F, Marchetti C, Palaia I, Musio D, Muzii L, Tombolini V, Panici PB. Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. J Immunol Res. 2015;2015:191832. doi: 10.1155/2015/191832. Epub 2015 Jul 7. PMID: 26236750; PMCID: PMC4508475.
2. Doo DW, Norian LA, Arend RC. Checkpoint inhibitors in ovarian cancer: A review of preclinical data. Gynecol Oncol Rep. 2019 Jun 18;29:48-54. doi: 10.1016/j.gore.2019.06.003. PMID: 31312712; PMCID: PMC6609798.